To grow beyond a size of 2-3 mm3, tumors have to recruit a neovasculature via angiogenesis. Tumors accomplish this via expression of Vascular Endothelial Growth Factor-A (VEGF-A), either induced by hypoxia in the tumor center or as a result of malfunctioning tumor suppressor gene products or activated proto-oncogenes. A number of compounds that target the VEGF-A signaling pathway has been developed with the aim to inhibit angiogenesis and, consequently, tumor growth. Although such anti-angiogenic therapies have been effective in animal tumor models, translation to the clinical level has so far proven to be less successful (M. E. Eichhorn et al., Drug Resist. Update 7:125-138 (2004)).
For this, there is a number of possible explanations. In clinically relevant situations, tumors may have been growing for months or even years at the time of diagnosis, and a significant proportion of the vasculature may be more or less mature and thus insensitive to angiogenesis inhibition. This situation is in sharp contrast to that in most animal models in which, as a rule, aggressive, fast-growing tumors are studied. Furthermore, patients that are candidates for anti-angiogenic therapy are typically patients with disseminated, uncontrollable cancer and growth of metastases may not always be strictly dependent on angiogenesis. Because most metastases are blood-borne, they grow out in organs with intrinsically high vessel densities like liver, lung and brain, where they can grow in an angiogenesis-independent fashion by co-option of pre-existent vessels.
Indeed, an angiogenesis inhibitor that very effectively inhibits tumor growth in a number of subcutaneous tumor models (S. R. Wedge et al., Cancer Res. 62:4645-4655 (2002)) does not inhibit growth of infiltrative tumors in mouse brain. Moreover, upon treatment of mice carrying highly angiogenic brain tumors, angiogenesis inhibition did not result in a halt of further tumor progression, but rather in a progression after a phenotypic shift toward co-option and infiltration (W. P. Leenders et al., Clin. Cancer Res. 10:6222-6230 (2004)). These results imply that anti-angiogenic therapy should be supplemented by vascular targeting therapies in which the existing tumor vascular bed is attacked, resulting in secondary tumor cell death due to disruption of the tumor's blood supply.
To accomplish effective vascular targeting therapy, markers have to be identified that have specificity for tumor vasculature. Much effort has already been put in this, but with varying success. Effective vascular tumor targeting has been accomplished using single chain antibodies, directed against the fibronectin ED-B domain, which is selectively expressed and deposited in the extracellular matrix of newly formed vessels in angiogenic tumors (M. Santimaria et al., Clin. Cancer Res. 9:571-579 (2003)). Targeting of a vβ3-integrin (the expression of which is restricted to immature vessels) using RGD peptides or Vitaxin yielded a disappointing result, whereas endoglin-expression was not specific for tumor blood vessels (J. A. Posey et al., Cancer Biother. Radiopharm. 16:125-132 (2001); E. Balza et al., Int. J. Cancer 94:579-585 (2001)).
In inflammatory diseases such as rheumatoid arthritis (RA) or atherosclerosis, angiogenesis and activation of the vasculature is also often part of the pathology. The vasculature here paves the way for inflammatory cells to extravasate and exert their destructive action. Such diseases can thus also benefit from targeting to blood vessels.